Inflammation-induced caveolin-1 and BMPRII depletion promotes endothelial dysfunction and TGF-[Beta]-driven pulmonary vascular remodeling

• Published in: American journal of physiology. Lung cellular and molecular physiology 2017-05, Vol.312 (5), p.L760
• Main Authors: Oliveira, Suellen D S, Castellon, Maricela, Chen, Jiwang, Bonini, Marcelo G, Gu, Xiaowu, Elliott, Michael H, Machado, Roberto F, Minshall, Richard D
• Format: Article
• Language: English
• Subjects: Albumin; Albumins; Bone morphogenetic protein receptor type II; Caveolin; Caveolin-1; Cell activation; Cells; Depletion; E coli; Endothelial cells; Exposure; Growth factors; Homeostasis; Immune system; Inflammation; Inflammatory response; Interleukin 6; Leakage; Lipopolysaccharides; Lungs; Microvasculature; Nitric oxide; Nitric-oxide synthase; Oxidative stress; Phosphorylation; Priming; Respiratory distress syndrome; Smad protein; Thickness; Transforming growth factor; Transforming growth factor-b
• ISSN: 1040-0605; 1522-1504

Endothelial cell (EC) activation and vascular injury are hallmark features of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Caveolin-1 (Cav-1) is highly expressed in pulmonary microvascular ECs and plays a key role in maintaining vascular homeostasis. The aim of this study was to determine if the lung inflammatory response to Escherichia coli lipopolysaccharide (LPS) promotes priming of ECs via Cav-1 depletion and if this contributes to the onset of pulmonary vascular remodeling. To test the hypothesis that depletion of Cav-1 primes ECs to respond to profibrotic signals, C57BL6 wild-type (WT) mice (Tie2.Cre-;Cav1^sup fl/fl^) were exposed to nebulized LPS (10 mg; 1 h daily for 4 days) and compared with EC-specific Cav1-/- (Tie2.Cre+;Cav1^sup fl/fl^). After 96 h of LPS exposure, total lung Cav-1 and bone morphogenetic protein receptor type II (BMPRII) expression were reduced in WT mice. Moreover, plasma albumin leakage, infiltration of immune cells, and levels of IL-6/IL-6R and transforming growth factor-β (TGF-β) were elevated in both LPS-treated WT and EC-Cav1-/- mice. Finally, EC-Cav1-/- mice exhibited a modest increase in microvascular thickness basally and even more so on exposure to LPS (96 h). EC-Cav1-/- mice and LPS-treated WT mice exhibited reduced BMPRII expression and endothelial nitric oxide synthase uncoupling, which along with increased TGF-β promoted TGFβRI-dependent SMAD-2/3 phosphorylation. Finally, human lung sections from patients with ARDS displayed reduced EC Cav-1 expression, elevated TGF-β levels, and severe pulmonary vascular remodeling. Thus EC Cav-1 depletion, oxidative stress-mediated reduction in BMPRII expression, and enhanced TGF-β-driven SMAD-2/3 signaling promote pulmonary vascular remodeling in inflamed lungs.